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NCT00382109 · CITED IN SOURCE DOCUMENTS

Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2019-08-07

This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host disease in young patients who are undergoing donor stem cell transplant for intermediate-risk or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It is not yet known whether tacrolimus and methotrexate are more effective with or without sirolimus in preventing graft-versus-host disease.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Estimated Percentage of Participants With Event Free Survival

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outcome · POSTED

Rate of Relapses

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outcome · POSTED

Estimated Transplant Related Mortality Percentage

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outcome · POSTED

Estimated Rate of Acute Graft VS Host Disease (GVHD)

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outcome · POSTED

Estimated Rate of Overall Chronic Graft VS Host Disease

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outcome · POSTED

Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation

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outcome · POSTED

Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)

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outcome · POSTED

Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)

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outcome · POSTED

Chimerism

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second complete remission (CR2) (M1 bone marrow, \< 5% blasts by morphology) meeting the following criteria: * Intermediate risk relapsed ALL in CR2 (may receive matched sibling transplantation only) meeting 1 of the following criteria: * B-lineage ALL in CR2 after a late first bone marrow (BM) relapse (≥ 36 months after the initiation of primary chemotherapy) with or without associated extramedullary disease * B-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy) * High risk relapsed ALL in CR2 (may receive other related donor, unrelated donor, or matched sibling transplantation) meeting 1 of the following criteria: * In CR2 after an early first BM relapse (\< 36 months from initiation of primary chemotherapy) * T-lineage ALL in CR2 after a first BM relapse occurring at any time after initiation of primary chemotherapy * Philadelphia chromosome-positive ALL in CR2 after a first BM relapse occurring at any time after the initiation of primary chemotherapy * T-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy) * High risk de novo ALL in CR1 (may receive matched sibling, other related/unrelated BM/PBSC or unrelated CB transplantation) meeting 1 of the following criteria: * Patients with the presence of t(9;22) translocation (Ph+) detected by cytogenetic or PCR analysis at initial diagnosis. For patients on AALL0622, the criteria for transplant are 1) any patient with Ph+ ALL with an available matched sibling donor or 2) any patient with Ph+ ALL that is defined as high risk (MRD \> 1% Day 29 or MRD \> 0.01% end-Consolidation Block 2) with any available donor, related or unrelated. Patients enrolled on AALL0622 are only eligible if they follow this algorithm. * Patients with the presence of extreme hypodiploidy (\< 44 chromosomes or DNA index of \< 0.81) detected by cytogenetic/ploidy analysis at initial diagnosis. * Patients with the presence of 11q23 (MLL) rearrangements detected by cytogenetic or PCR analysis at initial diagnosis who are slow early responders (M2/M3 at Day 14 or MRD \> 0.1% at Day 29). * Enrolled on an appropriate COG relapsed ALL clinical trial after completing the required study therapy (i.e., minimum 1 re-induction course (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks). Patients with high risk ALL in CR1 are eligible as soon as they have achieved a CR. * Patients not on a COG relapsed ALL clinical trial are eligible provided they have received ≥ 1 round of re-induction lasting 4-6 weeks and 1 round of intensive consolidation chemotherapy lasting 3-6 weeks * No B-cell ALL L3 morphology with evidence of myc translocation by molecular or cytogenetic technique * No Down syndrome * No evidence of active CNS or other extramedullary disease (i.e., no CNS2) * Karnofsky performance status (PS) 60-100% (for patients \> 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age) * Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram * ALT or AST \< 5 times upper limit of normal * Bilirubin \< 2.5 mg/dL (unless an increase is attributable to Gilbert's syndrome) * Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min * FEV\_1 ≥ 60% by pulmonary function tests (PFTs) * FVC ≥ 60% by PFTs * DLCO ≥ 60% by PFTs * For children who are unable to cooperate for PFTs all of the following criteria must be met: * No evidence of dyspnea at rest * No exercise intolerance * No requirement for supplemental oxygen therapy * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No HIV or uncontrolled fungal, bacterial, or viral infection * Fungal infection acquired during induction therapy allowed provided there is a significant response to antifungal therapy with minimal or no evidence of disease by CT scan * Other concurrent immunosuppressants allowed * No prior allogeneic or autologous stem cell transplantation * No prior or concurrent voriconazole unless prior voriconazole therapy is completed or a different agent is substituted for voriconazole prior to study entry * No concurrent grapefruit juice during sirolimus administration
healthy Volunteers
false
maximum Age
21 Years
minimum Age
1 Year
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.
    intervention Names
    1. Drug: thiotepa
    2. Drug: cyclophosphamide
    3. Drug: tacrolimus
    4. Drug: methotrexate
    5. Drug: sirolimus
    6. Radiation: total body irradiation
    label
    Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    type
    EXPERIMENTAL
  2. description
    Preparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
    intervention Names
    1. Drug: thiotepa
    2. Drug: cyclophosphamide
    3. Drug: tacrolimus
    4. Drug: methotrexate
    5. Radiation: total body irradiation
    label
    Tacro-MTX GVHD Prophylaxis
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Tacro-MTX GVHD Prophylaxis
    2. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Given IV
    name
    thiotepa
    other Names
    1. Oncotiotepa
    2. STEPA
    3. TESPA
    4. Tespamin
    5. TSPA
    type
    DRUG
  2. arm Group Labels
    1. Tacro-MTX GVHD Prophylaxis
    2. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Given IV
    name
    cyclophosphamide
    other Names
    1. CPM
    2. CTX
    3. Cytoxan
    4. Endoxan
    5. Endoxana
    type
    DRUG
  3. arm Group Labels
    1. Tacro-MTX GVHD Prophylaxis
    2. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Given IV or orally
    name
    tacrolimus
    other Names
    1. FK 506
    2. Prograf
    type
    DRUG
  4. arm Group Labels
    1. Tacro-MTX GVHD Prophylaxis
    2. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Given IV
    name
    methotrexate
    other Names
    1. amethopterin
    2. Folex
    3. methylaminopterin
    4. Mexate
    5. MTX
    type
    DRUG
  5. arm Group Labels
    1. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Given orally
    name
    sirolimus
    other Names
    1. AY 22989
    2. Rapamune
    3. rapamycin
    4. SLM
    type
    DRUG
  6. arm Group Labels
    1. Tacro-MTX GVHD Prophylaxis
    2. Tacro-MTX/Sirolimus GVHD Prophylaxis Regimen
    description
    Part of the transplant preparatory regimen
    name
    total body irradiation
    other Names
    1. TBI
    type
    RADIATION
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
146
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.
    measure
    Estimated Percentage of Participants With Event Free Survival
    time Frame
    at 2 years
secondary Outcomes
  1. description
    An event is defined as relapse.
    measure
    Rate of Relapses
    time Frame
    At 2 years
  2. description
    Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.
    measure
    Estimated Transplant Related Mortality Percentage
    time Frame
    100 days
  3. description
    Any grade acute graft vs host disease (defined in APPENDIX II study protocol).
    measure
    Estimated Rate of Acute Graft VS Host Disease (GVHD)
    time Frame
    At 200 days
  4. description
    Chronic graft vs host disease is defined in APPENDIX III of study protocol.
    measure
    Estimated Rate of Overall Chronic Graft VS Host Disease
    time Frame
    At 2 years
  5. description
    An event is defined as relapse or transplant-related mortality.
    measure
    Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation
    time Frame
    Up to 1 year
  6. description
    An event is defined as relapse; estimated probability of relapse.
    measure
    Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)
    time Frame
    At 1 year
  7. description
    An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.
    measure
    Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)
    time Frame
    At 2 months
  8. description
    Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.
    measure
    Chimerism
    time Frame
    Up to 12 months
Full study description
brief Summary
This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host disease in young patients who are undergoing donor stem cell transplant for intermediate-risk or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It is not yet known whether tacrolimus and methotrexate are more effective with or without sirolimus in preventing graft-versus-host disease.
detailed Description
PRIMARY OBJECTIVES: I. Compare the post-transplant 2-year event-free survival of pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete remission or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus. SECONDARY OBJECTIVES: I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients. II. Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by correlating ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of the mTOR pathway in patients treated with sirolimus, and altered resistance pathways in ALL blasts measured by microarray analysis. III. Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation by correlating the development of donor anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the detection of altered ALL blast immunogenicity after transplant with increased minimal residual disease, persistent recipient chimerism, and relapse. OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other related), and stem cell source (filgrastim \[G-CSF\]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs umbilical cord blood). PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily on days -8 to -6 and receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0. GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients are randomized to 1 of 2 treatment arms. ARM I: (experimental) Patients receive tacrolimus IV continuously or orally (when able) daily beginning on day -2 followed by a taper beginning on day 42 and continuing until day 98 (for patients undergoing matched sibling donor transplantation) OR tacrolimus IV continuously or orally daily beginning on day -2 followed by a taper beginning on day 100 and continuing until day 180 (for patients undergoing related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, and 6 (for patients with matched sibling and umbilical cord blood donors) OR days 1, 3, 6, and 11 (for patients with unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus daily beginning on day 0 followed by a taper beginning on day 180 and continuing until day 207. ARM II: (control) Patients receive tacrolimus and methotrexate as in arm I. After completion of study treatment, patients are followed periodically for approximately 5 years.
Source references
references
  1. citation
    Pulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, Kirsch I, Gastier-Foster JM, Borowitz M, Desmarais C, Williamson D, Kalos M, Grupp SA. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015 May 28;125(22):3501-8. doi: 10.1182/blood-2014-12-615757. Epub 2015 Apr 10.
    pmid
    25862561
    type
    DERIVED
  2. citation
    Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. doi: 10.1182/blood-2013-10-534297. Epub 2014 Feb 4.
    pmid
    24497539
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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        [<a href="#cit/section_10.96">96</a>]</p> <p id="_2267" tabindex="-1">A secondary analysis of the COG <a href="/clinicaltrials/NCT00382109">ASCT0431 (NCT00382109)</a> HSCT trial showed that ALL patients treated with TBI that involved dose modulation of lung fields to less than 8 Gy had a survival advantage on multivaria
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      source update dates
      1. context
        Updated: April 21, 2025
        datetime
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        display
        April 21, 2025

    Preserved source evidence · Not medical advice